Due to the persistent abuse of potent stimulants and the related adverse social and individual consequences, the overall objective of this Program Project is to elucidate the mechanisms responsible for the effects of potent stimulants of abuse, such as methamphetamine (METH) and cocaine (COC). In particular, the prevailing hypothesis to be tested by projects in this revised application is that METH and COC administration exert significantly different effects due to their distinct neurochemical mechanisms particularly to transporters and associated functions. We believe that by elucidating (a) the unique features of these two drugs, (b) their underlying mechanisms, and (c) the impact of their distinct properties, and other stimulants. The distinctive expertise at the University of Utah associated with the (a) Addiction Research and Education Center, (b) Anticonvulsant Screening Project, and (c) Center for Human Toxicology, enables to identify four principal projects that will test the overall hypothesis in a highly integrative fashion. The titles of the projects and their objectives are: i. Tolerance Induction (Project #1)-This project will determine the nature of the tolerance caused by escalating doses of METH, but not COC, and the effecting mechanism. ii. VMAT and Neurotoxicity (Project #2)-This project will determine how the opposite effects of METH and CC on VMAT contributes to the presence or absence of neurotoxicity. iii. Neuropeptides and Neurotoxicity (Project #3)-This project will examine the role of differential response by opioid peptide systems to METH and COC on the unique neurotoxic features of these stimulants. iv. Seizure Induction (Project #4)-This project will determine the unique features of seizures evoked by high doses of METH and COC and the underlying mechanisms. In a supportive role, the Administrative Core will function as the principal decision-making, evaluative, and administrative unit for this program; while the Resource Core will enhance efficiency and quality, and reduce expenses by providing high-quality, centralized animal and technology services for the project.